1. Field of the Invention
The present invention relates to the field of treating skin diseases. It particularly concerns a new method and composition for the treatment of psoriasis namely: psoriasis punctata, herpes simplex and mycosis fungoides, microbian eczema, acne, and, more generally, of benign or malignant skin proliferations.
2. Description of the Prior Art
Psoriasis is a rather frequent dermatosis of unknown etiology, with chronic evolution, and characterized by red, more or less wide, spots, well defined and covered by dry, numerous and brittle scales.
A recently-developed method for curing such diseases consists of administering certain furocoumarins (commonly called psoralens) either orally or topically. Of the active furocoumarins, 8-methoxypsoralen (hereinafter and usually referred to as 8-MOP) is used most widely in conjunction with exposure to near-ultraviolet light (around 365 nm). This treatment is known as PUVA-therapy.
This method provides good results but presents significant drawbacks. One of the most severe drawbacks, even if skin cancer had not been observed on patients previously treated with psoralen, is the potential danger of further involvement such as a skin cancer. This aspect has to be considered, as psoralens are powerful mutation inducers and some experiments effected on mice have shown that (after either topical or local administration) tumors were obtained on 100% of mice (GRIFFIN A. C., R. E. HAKIM and J. KNOX, J. Invest. Dermatol. 31/289-295,1958). Similar results were also indicated by F. URBACH, J. Invest. Dermatol. 32/373-378/1959. A more complete experiment was accomplished on two issues of hairless mice (JKH, hairless and HRS/J/AnC hairless) D. D. GREEBE, R. D. LEY et R. J. M. FRY in Photochem. and Photobiol. 25/269-276/1977 and confirmed the high cancerogenic power of 8-MOP in combination with U.V. radiation. Complementary results concerning this cancerogenic character of 8-MOP is provided hereinafter.
An object of this invention is to find products capable of curing previously-mentioned diseases without the noted drawbacks.
Complementary burning or blistering of the skin, dermatosis, gastric irritation, nausea, nervousness, insomnia and depression may occur with average doses of 8-MOP.
See, for example, "The Merck Index", Seventh Edition, p. 670; and M. A. Pathak; D. M. Kramer and T. B. Fitzpatrick (1974) in "Sunlight and Man", ed. M. A. Pathak, L. C. Harber, M. Seiji, A. Kukita, pp. 335-368, University Press, Tokyo.
The last-cited document indicates that the ability to sensitize cutaneous tissue to light appears to be a unique characteristic of the psoralen molecule having the following formula: ##STR2##
Complementary, it was stated that psoralen and methyl-substituted psoralen derivatives (substitution at 4-,4'-,5'- and 8-positions) are found to be most effective photo-sensitizers. Substitution by methyl or other groups at the 3 positions, however, does reduce the photosensitizing ability significantly.
For example, compounds such as 3,5',8-trimethylpsoralen, 3-methylpsoralen, 3,4,5',8-tetramethylpsoralen, 3,4-dibenzo-5,8-dimethylpsoralen, 3,4-cyclohexeno-5',8-dimethylpsoralen, and 3-n-butyl-4,5',8-trimethylpsoralen were found to be inactive or to induce very weak photosensitivity. More particularly, a psoralen derivative, such as 3-carboethoxypsoralen was mentioned as being completely inactive (table 2, p. 342) in view of its lack of photosensitizing ability.
It has been suggested that the sensitizing effect (in vivo and in vitro) of some furocoumarins was due to photoreactions with pyrimidine bases of nucleic acids.
Thus furocoumarins of the psoralen type have two photo-reactive sites, the 3,4 and the 4',5' double bonds, as indicated in the previously-noted formula. In the presence of 365 nm light mono-adducts with pyrimidines are formed, i.e. C.sub.4 -cyclo addition products involving the 5,6 double bond of pyrimidine are formed (2-4). Moreover, DNA cross-links are detected by several methods including the melting and renaturation pattern of treated DNA. It is assumed that the 3,4 and 4',5' double bonds of the psoralen derivatives are both involved in the formation of cross-links between pyrimidines of opposite DNA strands.
Up to recent years it was generally assumed that the main photosensitizing effects produced by psoralens were due to their ability to form cross-links in cellular DNA [Cole R. S.: "Light-induced Cross-linking of DNA in the Presence of a Furocoumarin", Biochim. Biophys. Acta, (Amst.) 217, 30-39 (1970)].
Consequently, it was commonly believed that it should not be possible to use monofunctional (that is to say 3,4- or 4',5'-substituted furocoumarins plus U.V. radiation for the treatment of skin diseases since such compounds do not form cross-linkages in DNA. This was confirmed by commonly-used tests in which the activity of psoralen derivatives with regard to skin diseases was estimated by observing the appearance of skin erythema after application of the product plus near-U.V. irradiation. The absence of an erythema was considered as proof for the absence of activity. Indeed some of the known mono-functional furocoumarins did not provocate an erythema.